The family of metabolites derived from the 5-lipoxygenase pathway (a.k.a. leukotrienes) has been characterized as pro-inflammatory deleterious molecules in numerous diseases (Shim et al., 2006; Vargaftig et al., 2003; Sayers et al., 2003; Peters-Golden et al., 2002; Avis et al., 2001; Profita et al., 2000; Wilborn et al., 1996; Sperling et al, 1992). Two major groups of downstream 5-lipoxygenase metabolites are cysteinyl leukotrienes (cLTs) (Capra et al., 2006; Asakura et al., 2004; Espinosa et al., 2003; Chibana et al., 2003; Ellis et al., 1994) and leukotriene B4 (LTB4). A rate-limiting enzyme for LTB4 synthesis, LTA4 hydrolase (LTA4H), has two catalytic activities, epoxyhydrolase activity (LTA4H EH activity), which channels upstream 5-lipoxygenase metabolites and synthesizes LTB4 (Stenson et al., 1984; Maycock et al., 1982), and aminopeptidase activity (LTA4H AP activity), which cleaves the N-terminus of different peptides. LTB4 exerts its biological effects through two known receptors, LTB4 receptor 1 and 2 (Del Prete et al., 2007; Pettersson et al., 2005; Gaudreault et al., 2005; Scott et al., 2004; Tarlowe et al., 2003; Jackson et al., 1999; Hullot et al., 1997; Showell et al., 1995; Fretland et al., 1995; Lawrence et al., 1994; Fretland et al., 1989).
To date, LTB4 has been considered a biomolecule that plays a major role in the chemotaxis and/or activation of neutrophils, monocytes, dendritic cells and lymphocytes at sites of inflammation. Therefore, over-production of LTB4 has been correlated with tissue damage and poor outcomes in diseases associated with neutrophilic and/or monocytic abnormal inflammation, diseases such as asthma (Turner et al., 1996; Radeau et al., 1990; Wardlaw et al., 1989), chronic obstructive pulmonary disease (COPD) (Profita et al., 2005; Hubbard et al., 1991; Tanno et al., 1988; O'Driscoll et al., 1984), cystic fibrosis (Lawrence et al., 1994; Carpagnano et al., 2003; Lawrence et al., 1993; Lawrence et al., 1992; Cromwell et al., 1982), inflammatory bowel diseases (Bouchelouche et al., 1995; Nielsen et al., 1987; Lobos et al., 1987), coronary artery disease (Linsel-Nitschke et al., 2008; Topol et al., 2006), acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) (Hicks et al., 2010; Loick et al., 1994; Sun et al., 1990; Sprague et al., 1990; Goldman et al., 1986), the common cold (Widegren et al., 2011; Kostikas et al., 2005; Callan et al, 1988), and inflammatory arthritis (Senoh et al., 1993; Sprague et al., 1989; Mehta et al., 1989; Mehta et al., 1987). Subsequently, pharmaceutical strategies included attempt to either inhibit production of LTB4 (including agents that provide for complete inhibition of LTA4H activities) or antagonize LTB4 receptors at local tissues. However, several large pharmaceutical studies with those agents yielded either conflicting or insignificant outcomes in human subjects (Diaz-Gonzalez et al., 2007; Hawkey et al., 1997; Roberts et al., 1997; Schmitt-Groho et al., 2005).